Metabolic Profiling of Immune Responses in Immune-mediated Diseases
Study Details
Study Description
Brief Summary
Background:
The immune system is the part of the body that fights infection. Some people have immune deficiencies that cause skin rashes, make them get sick often with infections, or make it difficult for their skin to heal. Researchers want to learn more to better treat conditions that affect immune response.
Objective:
To learn about how the immune system and skin healing are related to each other.
Eligibility:
People ages 18-75 with primary immune deficiency, eczema, or psoriasis. Healthy volunteers are also needed.
Design:
Participants will be screened with a medical and medicine history and a physical exam. They may take a pregnancy test.
Participants will discuss the medicines or supplements they take as well as skin products they use, such as soaps and lotions.
Participants will have up to 4 skin biopsies taken from the forearm. A needle will inject an anesthetic into the skin where the biopsy will be done. A sharp tool that looks like a tiny cookie cutter will be used to remove a round plug of skin a bit smaller than the tip of a pencil.
Participants will give at least 1 blood sample.
Participants may have optional skin swab collection. A cotton swab will be used to swab the skin on the arm.
Participants may have optional skin tape collection. A sticky strip of tape will be placed on the arm and then removed.
Participants may give leftover samples taken as part of their regular medical care.
Participation will last for about 4 days. Participants will have 2 visits that each last about 1 hour. They may be asked to repeat the study in the future.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
The primary objective of this research is to perform in vivo assessment of the metabolic signatures associated with immunity, with particular focus on the immune modulators of wound healing and tissue repair.
Perhaps the most demonstrative example of immune dysfunction resulting from metabolic disorder is that of adenosine deaminase (ADA) severe combined immune deficiency (SCID). While several other metabolic disruptions can also lead to SCID, ADA deficiency causes an intracellular accumulation of deoxyadenosine, which, among other actions, interferes with the VDJ rearrangement needed for proper lymphocyte function and contributes to cell apoptosis. Additional immune phenotypes have been described for monogenic or digenic disorders of glycerophospholipid metabolism, amino acid transport, glycosylation, and oxidative phosphorylation. Metabolic processes are also known to influence the function of T cells, dendritic cells, and macrophages. More recent work has also suggested that metabolic reprograming offers innate immune cells a form of memory, previously thought to be exclusive to the adaptive immune system.
In addition to metabolic signatures associated with immune defects, this protocol will provide insights into how these immune defects impact wound healing and tissue repair. Recent work from our group has suggested that metabolic imbalance downstream of STAT3 may drive both the reduced wound healing seen in patients with autosomal dominant hyperimmunoglobulin E syndrome (AD HIES) or atopic dermatitis as well as in keloid scarring disorder.
This sample collection protocol will enroll 50 to 150 adult participants who are healthy volunteers or patients with confirmed or suspected primary immunodeficiency, psoriasis, or atopic dermatitis. We will perform exploratory evaluations of metabolomics of immune mediated diseases in peripheral blood cells, serum, skin biopsies, skin tape strips, and skin swabs. We will contrast this host information with metabolomics of the microbiome as collected by RNA sequencing and mass spectrometry. Participants will have up to 4 skin punch biopsies from the forearm over the course of 4 days to capture wound healing progress and identify involved pathways. During the same timeframe, we will collect peripheral blood to assess the metabolic signature of immune cells and serum/plasma. This protocol will afford the ability to link known immune defects (monogenic or digenic immune disorders, atopic dermatitis, or psoriasis) with metabolic profiling. We will be able to link, within individual cell types, serum, and skin samples, how (as one example) mutations in STAT3 shift the metabolic responses. Ultimately, we expect to construct a searchable database directly linking immune pathways with their associated metabolic signatures in blood cells, serum, and skin.
We anticipate that the research will provide critical new information on the human skin immune and remodeling responses and will have direct relevance for the development of vaccines, diagnostics, and therapeutics. All research procedures will be performed at the National Institutes of Health Clinical Center.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Healthy volunteers Control group |
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| Patients with atopic dermatitis Physician-diagnosed atopic dermatitis |
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| Patients with primary immunodeficiency Confirmed by genetic diagnosis or suspected by genetic variant of unconfirmed significance and a history consistent with immunodeficiency |
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| Patients with psoriasis Physician-diagnosed psoriasis |
Outcome Measures
Primary Outcome Measures
- Change in relative abundance of microbial skin taxa and/or skin metabolites associated with wound healing or immune mediated disorders. [Throughout study]
Determine whether there are abnormalities in specific tissue repair pathways, such as epithelial to mesenchymal transition (EMT) are associated with immune-mediated disorders.
- Fold difference in metabolic pathways associated with immune pathways. [Throughout study]
Evaluate metabolic profiles in immune activation associated with known or suspected immune-mediated disorders.
- Fold differences in metabolic pathways related to wound healing. [Throughout study]
Determine whether there are abnormalities in specific tissue repair pathways, such as epithelial to mesenchymal transition (EMT) are associated with immune-mediated disorders.
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
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Meets one of the following:
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Has documentation of PID confirmed by genetic evaluation demonstrating a deleterious variant in the gene (or genes) known to be associated with immune deficiency (confirmed PID); or
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Has documented variant of undetermined significance in a gene (or genes) that is predicted to be deleterious in immune function by the investigators AND a clinical history of infections which are more frequent, more chronic, or more severe than normal (suspected PID); or
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Has physician-diagnosed psoriasis; or
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Has physician-diagnosed AD; or
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Does not have clinically apparent evidence of any monogenic or digenic immune defect, AD, or psoriasis (healthy volunteers).
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Aged 18 to 75 years.
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Willing to allow storage of blood, biopsy tissue, and bacterial and fungal cultures for future research.
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Able to provide informed consent.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
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Current or prior (within 3 months) anticoagulant or anti-platelet therapy (other than aspirin or non-steroidal anti-inflammatory drugs).
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Current or prior (within 3 months) use of immunomodulatory drugs (eg, chemotherapy, steroids), except if approved by the principal investigator.
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History of keloid formation.
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Pregnancy, lactating, or breastfeeding.
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Any condition that, in the opinion of the investigator, contraindicates participation in the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Principal Investigator: Ian A Myles, M.D., National Institute of Allergy and Infectious Diseases (NIAID)
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Dmitrieva NI, Walts AD, Nguyen DP, Grubb A, Zhang X, Wang X, Ping X, Jin H, Yu Z, Yu ZX, Yang D, Schwartzbeck R, Dalgard CL, Kozel BA, Levin MD, Knutsen RH, Liu D, Milner JD, López DB, O'Connell MP, Lee CR, Myles IA, Hsu AP, Freeman AF, Holland SM, Chen G, Boehm M. Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome. J Clin Invest. 2020 Aug 3;130(8):4167-4181. doi: 10.1172/JCI135490.
- McCann KJ, Yadav M, Alishahedani ME, Freeman AF, Myles IA. Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3. PLoS One. 2021 Mar 4;16(3):e0248011. doi: 10.1371/journal.pone.0248011. eCollection 2021.
- Myles IA, Castillo CR, Barbian KD, Kanakabandi K, Virtaneva K, Fitzmeyer E, Paneru M, Otaizo-Carrasquero F, Myers TG, Markowitz TE, Moore IN, Liu X, Ferrer M, Sakamachi Y, Garantziotis S, Swamydas M, Lionakis MS, Anderson ED, Earland NJ, Ganesan S, Sun AA, Bergerson JRE, Silverman RA, Petersen M, Martens CA, Datta SK. Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. Sci Transl Med. 2020 Sep 9;12(560). pii: eaaz8631. doi: 10.1126/scitranslmed.aaz8631.
- 10000392
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